Genetics of Bowel Cancer

As can be deduced from the adenoma - carcinoma sequence (polyp / carcinoma sequence), besides factors critical only to adenoma progression, the aetiology of colorectal adenomatous polyps should be the same as that for colorectal cancer - the adenoma just being an intermediate step in the development of cancer.

Indeed, there are well recognised inherited syndromes characterised by multiple colorectal adenomas that invariably give rise to colorectal cancer.  These cases are uncommon and only constitute about 5% of reported cancers.

There is increasing evidence however that many adenoma cases have some previously unrecognised genetic predisposition with absolute adenoma risk being modified by environmental factors.

Genetic Syndromes

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a rare autosomal dominant syndrome characterised by hundreds or even thousands of adenomatous colorectal polyps affecting approximately 1 in 10,000 individuals.  Untreated these polyps almost invariably progress to carcinoma by a mean age of 44.  Mutations are found in the APC (adenomatous polyposis  coli) gene which is located on chromosome 5q and penetrance is thought to approach 100%.  Mutation at the APC locus appears to be a common event in colorectal cancer induction, the only difference there being that in FAP-associated lesions there is an inherited genetic defect.

The designation Gardner Syndrome is used for phenotypic variants of FAP with additional extra colonic manifestations e.g. osteomas, epidermoid cysts and fibromas and Turcot's syndrome for the association with medulloblastoma.

The APC gene on chromosome 5

Phenotypical variation in FAP is now known to depend on the location of the APC mutation.  Attenuated FAP, in which there are relatively few polyps, is associated with mutations in codons at the 5' end of the APC gene whereas mutation between codon 1285 and 1465 result in profuse polyposis syndrome.  The best example of this variation giving rise to extra colonic features is the presence of Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) which is associated with mutations in codons 542 to 1309.

HNPCC is an autosomal dominant syndrome that is estimated to be responsible for approximately 2% of colorectal cancers.  The syndrome is characterised by familial clustering of colorectal cancers along with other cancers such as endometrium, ovary, gastric, hepatobiliary and renal tract.  In the absence of a clear phenotype an absolute definition of HNPCC is therefore obviously difficult - the Amsterdam Criteria and Bethesda Criteria attempt to classify on clinical grounds those families most at risk of having mutation in the mismatch repair genes that give rise to HNPCC

Non-coding regions of DNA exhibit variation which principally consists of highly repetitive segments of DNA consisting of several iterations of a specific sequence known at "DNA repeats".  Such sequences are unique to each person and are the basis for the precise DNA fingerprinting used in forensics.  These repeats of 2-5 nucleotide segments are known as microsatellite DNA.  A single pair of PCR oligonucleotide primers that surround such sequences produce variably-sized DNA fragments depending upon the number of repeats.

The mismatch repair pathway is responsible for detecting and repairing short segments of mismatched base pairs (such as a mutation from C to T on one strand T opposite G, or the addition of extra nucleotides, resulting in unpaired bases within the helix)⁵⁵. Since microsatellite repeats are susceptible to such mutation, disorders of the mismatch repair pathway lead to errors in these polymorphic segments - termed microsatellite instability (MSI).

In HNPCC, microsatellite instability was discovered to be the result of germline mutations in the genes that encode the components of the DNA proofreading complex. These genes are hMSH2, hMLH1, hPMS1, and hPMS2.  hMSH2 and hMLH1 are the most commonly mutated in HNPCC, whereas mutation in the genes hPMS1 and hPMS2 contribute only to a small proportion of cases.  The resultant colorectal cell lines show a higher accumulation of other mutations and deletions presumably reflecting the in vivo accumulation of errors resulting in an increased risk of cancer.